Montelukast is a selective, orally active leukotriene receptor antagonist that inhibits the cysteinyl leukotriene CysLT1 receptor. Leukotrienes are associated with the inflammation and constriction of airway muscles and the accumulation of fluid in the lungs. Montelukast sodium is a useful therapeutic agent for treating respiratory diseases such as asthma and allergic rhinitis.
The chemical name for montelukast sodium is: [R -(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetic acid, monosodium salt. Montelukast sodium salt is represented by the formula:
Montelukast sodium as marketed is a hygroscopic, optically active, white to off-white powder. Montelukast sodium is freely soluble in methanol, ethanol, and water and practically insoluble in acetonitrile.
U.S. Pat. No. 5,565,473 discloses a synthetic process for montelukast sodium, wherein the compound is obtained as an oil that is then dissolved in water and freeze-dried. The preparation method of the '473 patent is published at M. Labelle, et al. Bioorg. Med. Lett., 5 (3) 283-288 (1995). The synthesis method can be altered to allow for the preparation of montelukast related compounds. O. King, et al. J. Org. Chem., 58: 3731-3735 (1993).
U.S. Pat. No. 5,614,632 claims a method of synthesis where montelukast is obtained by the nucleophilic substitution of a chiral mesitylate group with the dilithium dianion of the 1-(mercaptomethyl) cyclopropaneacetic acid with simultaneous inversion of configuration. It is highly desirable to preserve the chirality of the product, that is, to avoid racemization. In the '632 patent the formation of the dilithium dianion is realized with butyl lithium. U.S. Pat. No. 5,523,477 claims an improved method for the preparation of 1-(mercaptomethyl) cyclopropaneacetic acid.
Because butyl lithium is a dangerous and expensive reagent, there is a need for other methods for preparing montelukast that utilize other reagents while preserving the chirality of the product.